Age-related macular degeneration (AMD) is the leading cause of acquired blindness in the United States. Patients with early disease suffer from limited and ineffective options for prevention and treatment. To address this shortcoming, this proposal focuses on the mechanisms underlying early disease. Cigarette smoking is the strongest epidemiological link with AMD, yet we do not fully understand its role in the pathophysiology of this disease. Cigarette smoke is a powerful chemical oxidant, and a potent inducer of complement activation. Both of these factors are thought to be important in AMD development. A key early event in AMD is apoptosis of the retinal pigmented epithelium (RPE), in part through inadequately neutralized oxidative stress. Nuclear factor- erythroid 2-related factor 2 (Nrf2), a basic leucine zipper redox-sensitive transcription factor, regulates the inducible expression of antioxidant and cytoprotective genes by binding to the cis-acting enhancer sequence known as the antioxidant response element. Normally, Nrf2 levels are low, but with an oxidative stimulus, nuclear accumulation of Nrf2 increases after it is released from its cytoplasmic inhibitor Keap1, and activates the coordinated transcription of its downstream antioxidant enzymes. Decreased Nrf2 signaling is seen in aging and disease, resulting in an inadequate adaptive stress response. Intriguingly, the decreased Nrf2 activity can be reversed by the synthetic triterpenoid derivatives of oleonolic acid, which represent a promising new class of agents for cytoprotection from oxidative injury. In this proposal, we hypothesize that chronic cigarette smoking induces persistent oxidative stress in the fundus, and that local Nrf2 signaling becomes inadequate with the onset of AMD. Recently, we showed that chronic cigarette smoke induces oxidative and ultrastructural damage, and eventually apoptosis to the RPE of mice. We will exploit this system using genetically modified mice to address our hypothesis with the following aims: 1) To test the hypothesis that Nrf2 signaling protects against cigarette smoke-induced oxidative stress and apoptosis in the fundus. 2) To investigate the hypothesis that regulation by Nrf2 signaling on complement activation determines the damage and apoptosis to the fundus that is induced by cigarette smoke. 3) To determine if a pharmacological activator of Nrf2 protects the fundus from oxidative damage and complement activation.